Immunization With Plasmodium Falciparum Sporozoites Under Chloroquine Versus Mefloquine Prophylaxis

Malaria Clinical Trial

Official title:

Immunization With Plasmodium Falciparum Sporozoites Under Chloroquine Versus Mefloquine Prophylaxis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01422954
• Other study ID #: ZonMw2
• Status: Completed
• Phase: N/A
• First received: August 23, 2011
• Last updated: April 26, 2013
• Start date: January 2012
• Est. completion date: April 2013

Study information

• Verified date: April 2013
• Source: Radboud University
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial Summary

Malaria is one of the major infectious diseases in the world with a tremendous impact on the quality of life, significantly contributing to the ongoing poverty in endemic countries. It causes 800.000 deaths per year, the majority of which are children under the age of five. The malaria parasite enters the human body through the skin, by the bite of an infected mosquito. Subsequently, it invades the liver and develops and multiplies inside the hepatocytes. After a week, the hepatocytes burst open and the parasites are released in the blood stream, causing the clinical phase of the disease.

As a unique opportunity to study malaria immunology and efficacy of immunisation strategies, a protocol has been developed in the past to conduct controlled human malaria infections (CHMIs). CHMIs generally involve small groups of malaria-naïve volunteers infected via the bites of P. falciparum infected laboratory-reared Anopheline mosquitoes. Although potentially serious or even lethal, P. falciparum malaria can be radically cured at the earliest stages of blood infection when risks of complications are virtually absent.

The investigators have shown previously that healthy human volunteers can be protected from a malaria mosquito (sporozoite) challenge by immunization with sporozoites (by mosquito bites) under chloroquine prophylaxis (CPS immunization). Interestingly, sterile protection in 100% of the human CPS immunized volunteers was achieved by a relatively miniscule dose, i.e. a total of 45 infectious mosquito bites, strikingly 20-fold more potent than the 1000 bites needed in a model using irradiated mosquitoes. One possible explanation for this efficient induction of protective immunity, is the immune modulating effect of chloroquine. The investigators aim to assess this possible immune modulating effect in CPS immunization by comparing immunization with P. falciparum sporozoites under chloroquine with immunization under mefloquine prophylaxis, which has the same antimalarial effect, but not the immune modulating effects known from chloroquine.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: April 2013
• Est. primary completion date: December 2012
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 35 Years

Eligibility

Inclusion Criteria:

1. Age > 18 and < 35 years healthy volunteers (males or females)

2. Good health based on history and clinical examination

3. Negative pregnancy test

4. Use of adequate contraception for females

5. Signing of the informed consent form, thereby demonstrating understanding of the meaning and procedures of the study

6. Agreement to inform the general practitioner and to sign a request to release medical information concerning contra-indications for participation in the study

7. Willingness to undergo a Pf controlled infection through mosquito bites

8. Agreement to stay in a hotel room close to the trial center during a part of the study (Day 5 after challenge till treatment is finished)

9. Reachable (24/7) by mobile phone during the whole study period

10. Available to attend all study visits

11. Agreement to refrain from blood donation to Sanquin or for other purposes, during the whole study period

12. Willingness to undergo HIV, hepatitis B and hepatitis C tests

13. Negative urine toxicology screening test at screening visit and the day before challenge

14. Willingness to take a prophylactic regime of chloroquine or mefloquine and curative regimen of Malarone®

Exclusion Criteria:

1. History of malaria

2. Plans to travel to malaria endemic areas during the study period

3. Plans to travel outside of the Netherlands during the challenge period

4. Previous participation in any malaria vaccine study and/or positive serology for Pf

5. Symptoms, physical signs and laboratory values suggestive of systemic disorders including renal, hepatic, cardiovascular, pulmonary, skin, immunodeficiency, psychiatric, and other conditions which could interfere with the interpretation of the study results or compromise the health of the volunteers

6. History of diabetes mellitus or cancer (except basal cell carcinoma of the skin)

7. History of arrhythmias or prolonged QT-interval

8. Positive family history in 1st and 2nd degree relatives for cardiac events < 50 years old

9. An estimated, ten year risk of fatal cardiovascular disease of =5%, as estimated by the Systematic Coronary Risk Evaluation (SCORE) system

10. Clinically significant abnormalities in electrocardiogram (ECG) at screening

11. Body Mass Index (BMI) below 20 or above 30 kg/m2

12. Any clinically significant deviation from the normal range in biochemistry or hematology blood tests or in urine analysis

13. Positive HIV, HBV or HCV tests

14. Participation in any other clinical study within 30 days prior to the onset of the study

15. Enrollment in any other clinical study during the study period

16. For women: pregnancy or lactation

17. Volunteers unable to give written informed consent

18. Volunteers unable to be closely followed for social, geographic or psychological reasons

19. History of drug or alcohol abuse interfering with normal social function

20. A history of treatment for psychiatric disease or moderate or severe psychological episode in volunteer

21. A history of convulsions in volunteer

22. Severe depression, anxiety disorder of psychosis in first or second degree family

23. Contra-indications to Malarone®, chloroquine or mefloquine including hypersensitivity or treatment taken by the volunteer that interferes with Malarone®, chloroquine or mefloquine

24. The use of chronic immunosuppressive drugs, antibiotics, or other immune modifying drugs within three months of study onset (inhaled and topical corticosteroids and oral anti-histaminic are allowed) and during the study period

25. Any confirmed or suspected immunosuppressive or immunodeficient condition, including asplenia

26. Co-workers or trainees of the departments of Medical Microbiology, Parasitology, or Internal Medicine of the Leiden University medical Centre

27. A history of sickle cell anemia, sickle cell trait, thalassemia, thalassemia trait or G6PD deficiency

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Malaria
• Plasmodium Falciparum

Intervention

Drug:
• Chloroquine prophylaxis
Standard prophylactic regime: a loading dose of 300 mg on day 14 and day 17 and then 300 mg once a week, starting on day 21, for a total duration of 13 weeks. On day 0, day 3, day 7 and day 10, this group will receive a placebo.
• Mefloquine prophylaxis
Mefloquine prophylaxis, starting with a loading regime of split doses during the first three weeks: 125 mg on day 0, day 3, day 7, day 10, day 14 and day 17 and 250 mg once a week from day 21 onwards for a total duration of 13 weeks.

Biological:
• Immunization
Group 1 and 2 will receive three immunizations with Plasmodium falciparum infected mosquito-bites. Group 3 will receive an equal number of uninfected mosquito-bites.
• Controlled Human Malaria Infection
Exposure to the bites of 5 Plasmodium falciparum infected mosquitoes.

Drug:
• Malarone
When thick smear positive, of ar day 21 after challenge, all volunteers will be treated with malarone.

Locations

Country	Name	City	State
Netherlands	Leiden University Medical Centre	Leiden

Sponsors (2)

Lead Sponsor	Collaborator
Radboud University	ZonMw: The Netherlands Organisation for Health Research and Development

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Duration of prepatent period after challenge infection as measured by microscopy		21 days after challenge (day 239 of the study)	No
Secondary	Development of parasitemia as measured by PCR		21 days after challenge (day 239 of study)	No
Secondary	Frequency of signs or symptoms in study groups		Day 0 - day 358 of study	Yes
Secondary	Cellular immune responses between study groups		Day 0 -day 358 of study	No
Secondary	Humoral immune responses between study groups		Day 0 - 358	No

External Links

•   Roestenberg et al. Long-term protection against malaria after experimental sporozoite inoculation: an open-label follow-up study. Lancet 2010.
•   Roestenberg et al. Protection against a Malaria Challenge by Sporozoite Inoculation, NEJM 2009.